Methods reported previously for the determination of encainide and its metabolites in biological fluids have not been extensively described and evaluated. We report an improved high-performance liquid chromatographic assay for the quantification of these compounds in plasma and urine with complete estimation of the accuracy and reproducibility of the analytical method. The major improvements consist of: (1) the use of ethaverine as an appropriate internal standard; (2) the use of the salting-out technique which improves the extraction recovery for the metabolites of encainide and the sensitivity of the assay; and (3) a shift of the ultraviolet absorption wavelength from 254 to 270 nm to increase the selectivity of the detection.